The long-term goals of this research are to determine the three dimensional structures and the amino acid sequences of M components and to investigate the interrelationship between the two by means of energy calculations. The proteins for this study will be obtained from patients with monoclonal gammopathies, including mostly those with malignancies involving multiple syeloma, Waldenstrom's macroglobulinemia, or cryoglobulinemia. An interdisciplinary approach is being followed which involves X-ray crystallography, biochemistry, theoretical energy calculations, and conformational analysis. The specific aims for the crystallographic component are to refine Rhe to 1.6 Angstrom resolution, to solve the structures of Pav and Fc Wat, to compare known immunoprotein structures and to search for new Igs. Energy calculations and conformational analysis will be used to refine the structures of Rhe and Rei, to see whether the nonhypervariable regions in Rhe and Rei can assume the tertiary structure of the other, study pertubations of the non-hypervariable residues caused by stereochemical changes in the hypervariable regions, and to relate 3D structure to AA sequence. The biochemical part of the study has for its specific aims to determine the AA sequences of Rhe and Pav, to do additional fragmentation experiments on IgG Wat, IgG Bar, and IgG Whi. Attempts will be made to explain the usual solubility of Bar and to locate the 25 to 30 extra AA residues in Whi, a cryoglobulin. An objective will be to test our recent hypothesis stating that the variability and diversity in the 3D structure of antibodies extends beyond the hypervariable lo ps to include a nonhypervariable loop and the mode of VL-VH association. The unification of biochemical and crystallographical knowledge through the use of energy calculations should have a great impact in our understanding nature's design of the antibody molecule.